IDENTIFYING THE PAPILLON LEFEVRE SYNDROME GENE DEFECT

识别巴比龙勒菲佛综合症基因缺陷

• 批准号: 6362938
• 负责人: Thomas C Hart
• 金额: $ 19.29万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-03-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6362938
• 关键词: chromosomes; clinical research; diagnosis design /evaluation; family genetics; gene expression; gene mutation; genetic disorder diagnosis; genetic markers; genotype; gingiva; homozygote; human genetic material tag; human subject; keratosis; linkage mapping; nucleic acid sequence; periodontitis; polymerase chain reaction

In this study we propose to identify the genetic mutation(s) responsible for Papillon Lefevre syndrome (PLS). PLS is a hereditary condition characterized by diffuse transgradiens palmoplantar keratosis and severe, early onset periodontitis resulting in premature loss of both the deciduous and permanent teeth. Treatment of PLS, particularly of the dental component, is difficult and of limited success. PLS is inherited as a simple autosomal recessive Mendelian trait. The gene responsible for PLS has not been identified, and the molecular basis for PLS is unknown. To date investigations of the cause of PLS have been limited to case reports of small numbers of individuals. Although a number of immunological anomalies have been reported for PLS, the lack of standardized approaches makes it difficult to extrapolate results of various studies and apply this information to develop better treatments or to understand what is causing the underlying pathology. A better strategy to understand the biologic basis of the condition is to first identify the gene and associated mutation(s) responsible for PLS. Recently, a PLS gene has been reported to be localized to an 8-10 cM region of chromosome 11q. We have also, independently localized the gene for PLS to chromosome 11q. We have studied 10 consanguineous families with PLS using homozygosity mapping to sublocalize a PLS gene to a 4-5 cM region of chromosome 11q. All 10 families we have studied to date appear to have a gene defect linked to the same region. We have identified 10 additional consanguineous families with PLS. These 20 PLS families represent the largest PLS population ever studied. We propose 3 broad strategies to identify the gene mutation(s) responsible for PLS. We will continue gene mapping studies to further refine the genetic candidate region for the PLS gene(s) (Specific Aim number 1). We propose molecular studies to resolve physical and genetic maps of the candidate region to help identify candidate genes and ESTs for the PLS locus (Specific Aim number 2). Strategies for gene identification and mutational analysis will then be used to evaluate genes and identify the specific mutation(s) responsible for PLS in these families (Specific Aim number 3). Completion of these Specific Aims should allow us to identify the gene responsible for PLS, and provide important information to understand its biologic basis. Identification of the genetic basis of PLS has implications for diagnosis and treatment of PLS and may provide insight into the increased susceptibility to periodontal destruction in other forms of periodontal diseases, particularly severe types that are less responsive to treatment.

在这项研究中，我们建议确定导致乳头状Lefevre综合征(PLS)的基因突变(S)。PL是一种遗传性疾病，其特征是弥漫性变性掌足角化和严重的早发性牙周炎，导致乳牙和恒牙过早丧失。偏头痛的治疗，特别是牙科部位的治疗是困难的，而且成功有限。PLS是一种简单的常染色体隐性孟德尔遗传。导致偏最小二乘的基因尚未确定，偏最小二乘的分子基础也不清楚。迄今为止，对该病原因的调查仅限于少数人的病例报告。尽管已有一些免疫异常的报道，但由于缺乏标准化的方法，很难推断各种研究的结果，并应用这些信息来开发更好的治疗方法或了解导致潜在病理的原因。要了解该病的生物学基础，更好的策略是首先确定导致该病的基因和相关突变(S)。最近，有报道将一个PLS基因定位在染色体11q的8-10 cM区域。我们还独立地将偏最小二乘基因定位于染色体11q。我们用纯合子作图的方法研究了10个偏最小二乘家系，将一个偏最小二乘基因定位在染色体11q的4-5 cM区域。到目前为止，我们研究的所有10个家族似乎都有与同一区域相关的基因缺陷。我们已经确定了另外10个有血缘关系的家系。这20个家系代表了迄今为止研究过的最大的群体。我们提出了三种广泛的策略来识别导致偏头痛的基因突变(S)。我们将继续进行基因定位研究，以进一步精炼偏最小二乘基因(S)的候选遗传区域(特定目标编号1)。我们建议进行分子研究，以解决候选区域的物理和遗传图谱，以帮助识别LS基因座(特定目标编号2)的候选基因和EST。然后将使用基因识别和突变分析的策略来评估基因并识别导致这些家族(特定目标编号3)中的PLS的特定突变(S)。这些特定目的的完成将使我们能够确定与LS有关的基因，并为了解其生物学基础提供重要信息。明确牙周病的遗传基础对诊断和治疗牙周病具有重要意义，并有助于了解其他牙周病，尤其是对治疗反应较差的严重牙周病对牙周破坏的易感性增加。

项目成果

An integrated physical and genetic map of the PLS locus interval on chromosome 11q14.

染色体 11q14 上 PLS 基因座区间的综合物理和遗传图谱。

• DOI: 10.1007/s003350010046
• 发表时间: 2000
• 期刊: Mammalian genome : official journal of the International Mammalian Genome Society
• 作者: Hart,TC;Walker,SJ;Bowden,DW;Hart,PS;Callison,SA;Bobby,PL;Firatli,E
• 通讯作者: Firatli,E